Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. This is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue.
Angiogenesis is traditionally classified as either sprouting angiogenesis or intussusception, or splitting angiogenesis. Sprouting angiogenesis forms entirely new blood vessels, whereas splitting angiogenesis split an existing blood vessel into two.
Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair.
The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies and pro-angiogenic therapies. Whereas anti-angiogenic therapies are being employed to treat or prevent cancer and malignancies, which require an abundance of oxygen and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat, for instance, cardiovascular diseases, coronary artery disease, atherosclerotic diseases, coronary heart disease, peripheral arterial disease, wound healing disorders, etc.
Traditional approaches in pro-angiogenic treatment include, among others, gene therapy, targeting genes of interest for amplification or inhibition; protein therapy, which primarily manipulates angiogenic growth factors; and cell based therapies, which involve the implantation of specific cell types.
There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity, inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis.
Pro-angiogenic protein therapy uses various growth factors, such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF), to promote angiogenesis. An obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell based pro-angiogenic therapies are still in early stages of research, with many open questions regarding best cell types and dosages to use.
Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. It also means local anemia and hypoxia in a given part of a body sometimes resulting from congestion, such as vasoconstriction, thrombosis or embolism.
Restoration of coronary blood flow after a period of prolonged ischemia often involve so-called reperfusion injury causing endothelial damage and an affected endothelium that takes on pro-coagulant and pro-inflammatory phenotype. The reperfusion greatly accelerates ischemia-induced complement activation and deposition.
Dextran sulfate is a well-known complement inhibitor and has therefore been proposed to achieve cytoprotection of endothelium against reperfusion injury following ischemia.
Experimental Cell Research 215, 294-302 (1994) discloses that sulfated polysaccharides, such as heparin and dextran sulfate, can be used in vitro for collagen-induced vascular tube formation. However, in vivo experimental data indicated that the low molecular weight sulfated polysaccharide heparin (2.4 kDa) inhibited angiogenesis, Glycobiology 3, 567-573 (1993), Pathophysiology of Haemostasis and Thrombosis 23, 141-149 (1993).
U.S. Pat. No. 5,135,920 discloses that dextran sulfate with an average molecular weight of 500 000 Da is angiostatic, i.e. inhibits angiogenesis.
There is still room for improvements within the field of angiogenesis in the art.